Peroxisome proliferator-activated receptors are lipid-activated nuclear receptors that heterodimerize with retinoid X receptors to modulate transcription at target gene promoters. Work over the past decade has defined multiple roles for the PPARs in the regulation of lipid and glucose metabolism. Additionally, PPARg and PPARd are expressed in macrophages and appear to have roles in atherosclerosis. I plan to further examine the functions of PPARg and PPARd in macrophage biology and atherosclerosis with three series of experiments. The first set of experiments will explore the mechanism underlying PPARg-mediated atheroprotection. Specifically, I will test whether these effects are dependent upon a related class of nuclear receptors, known as liver X receptors. In the second set of studies, I will examine the effects of synthetic PPARd agonists on atherosclerosis. I have already performed a pilot study with such drugs, and they appear to be atheroprotective in mice. In a third series of experiments, I plan to determine the roles of PPARg and PPARd in acute immune responses by challenging PPAR-deficient mice with a panel of different pathogens. Such insights may also be relevant to the inflammatory roles of PPARs in atherosclerosis.